Articular cartilage has a role as a joint lubricant for absorbing impact at the diarthrodial joints during articular movement. The mechanical functions of the cartilage are imparted by the cartilage extracellular matrix constructed from type II and type XI collagens, and collagenous fibrils such as proteoglycan. It is known that the cartilage extracellular matrix is produced by the chondrocytes intrinsic to the cartilage.
Osteoarthritis is a typical cartilage tissue disease, caused by the aggravation of wear, damage, and degeneration of the articular cartilage in response to mechanical stresses (such as repetitive loading, excessive exercise, and trauma) and aging. The symptoms of osteoarthritis include joint pain during joint movement (movement pain) and a restricted range of motion (restricted motion), which lower the quality of daily life. In Japan, osteoarthritis affects about 20% of the population over the age 50, and is expected to affect more people as the medical development and improved lifestyle are expected to raise the average life expectancy. Osteoarthritis thus poses a big challenge in the aging society.
Conventional osteoarthritis therapies employ resting to prevent aggravation of symptoms or controlling pain by, for example, the administration of antiphlogistic analgetics or supplements, or the intraarticular administration of joint lubricants. These methods, however, are only supportive, and do not represent a definitive therapy, because the chondrocytes have only weak repairing capabilities (see Non-Patent Literature 1), and cannot regenerate cartilage tissue. A procedure using a metallic artificial replacement joint has been practiced for osteoarthritis cases with progressive cartilage degeneration. However, artificial joints have a number of drawbacks, including a heavy burden put on patients during the procedure, deterioration due to wear, a tendency to dislocate, and possible revision surgery necessitated by a loosened artificial joint.
Recently, a technique that enables a definitive treatment of osteochondrosis deformans through cartilage tissue regeneration has caught attention for the treatment of osteochondrosis deformans which does not respond well to conventional therapies. For such a technique to be realized, development of an easy-to-obtain cell supply source that can produce large numbers of cells while retaining the capability to differentiate and form cartilage tissue is urgently needed (see Non-Patent Literatures 2 and 3). Chondrocytes are considered as a good candidate for such a cell supply source used for cartilage tissue regeneration. However, because chondrocytes are limited in number and cause dedifferentiation through monolayer expansion (see Non-Patent Literature 4), recent studies focus more on the development of a technique that induces formation of cartilage tissue with the use of bone marrow-derived mesenchymal stem (MS) cells or embryonic stem (ES) cells (see Non-Patent Literatures 5 to 7). However, MS cells have only limited proliferative capabilities, and recent studies suggest that the cartilage produced from MS cells is unstable, and lacks sufficient cartilage properties (see Non-Patent Literatures 8 and 9). With regard to ES cell-derived differentiated cells, there are concerns that the cells, as an inhomogeneous population, may fail to provide sufficient cartilage tissue functions (see Non-Patent Literatures 10 and 11), or may cause formation of teratoid tumors (see Non-Patent Literature 12).
There are also reports of a technique that has brought innovation in the field of regenerative medicine, specifically a technique that reprograms and induces somatic cells to induced pluripotent stem (iPS) cells by introducing Oct3/4, Klf4, c-Myc, and Sox2 coding genes into the somatic cells (see Patent Literature 1, Non-Patent Literatures 13 to 24). However, because of the pluripotency of iPS cells, use of iPS cells for cartilage tissue regeneration requires the establishment of a technique that enables the cells to differentiate into a homogeneous chondrocyte population, and there are still technical problems that need to be solved for practical applications in cartilage tissue regeneration.
Over these backgrounds, there is a growing need for the development of cells that can be directly induced to only chondrocytes, and that have cartilage tissue regenerative capabilities and a proliferative ability, and for a cell supply source that can also be used for a definitive treatment of osteochondrosis deformans.